Research ArticleAlzheimer’s Disease

Reduced non–rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease

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Science Translational Medicine  09 Jan 2019:
Vol. 11, Issue 474, eaau6550
DOI: 10.1126/scitranslmed.aau6550
  • Fig. 1 Mean amyloid pathology for the 38 participants with PET imaging.

    Mean AV-45 amyloid pathology in (A) all, (B) amyloid-negative, and (C) amyloid-positive subjects as measured in SUVR units after partial volume correction using a regional spread function (rsf).

  • Fig. 2 Mean tau pathology for the 38 participants with PET imaging.

    Mean AV-1451 tau pathology in (A) all, (B) tau-negative, and (C) tau-positive subjects as measured in SUVR units after partial volume correction using a regional spread function.

  • Fig. 3 Regional differences in the relationship between NREM SWA and tau PET.

    Regional differences in NREM SWA at 1 to 4.5 Hz (A), 1 to 2 Hz (B), 2 to 3 Hz (C), and 3 to 4 Hz (D) on AV-1451 tau PET after correction for multiple comparisons for the 38 participants with PET imaging. Linear mixed models were performed with NREM SWA as dependent variable and covariates age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time. Each AV-1451 tau PET region was included in the model individually and was corrected for multiple comparisons. The P value in the model from each region was mapped on a brain image and transformed to a logarithmic scale (P < 0.05 = >1.30).

  • Table 1 Participant characteristics.

    PET imagingCSF
    Mean (SD)/n (%)
    (N = 38)
    Mean (SD)/n (%)
    (N = 104)
    Age (years)73.8 (5.3)74.57 (5.20)
    Sex
      Men
      Women
    18 (47.4)
    20 (52.6)
    59 (56.7)
    45 (43.3)
    Race
      African-American
      Caucasian
      Asian
      More than one
    3 (7.9)
    35 (92.1)
    0 (0.0)
    0 (0.0)
    11 (10.6)
    92 (88.5)
    0 (0.0)
    1 (1.0)
    CDR
      0
      0.5
    29 (76.3)
    9 (23.7)
    83 (79.8)
    21 (20.2)
    ApoE4
      Negative
      Positive
    25 (65.8)
    13 (34.2)
    58 (55.8)
    45 (43.3)
    Sleep medications
      Yes
      No
    4 (10.5)
    34 (89.5)
    12 (11.5)
    92 (88.5)
    AHI (respiratory events/hour)*
      Negative (AHI < 5)20 (52.6)38 (36.5)
      Mild (AHI 5–15)13 (34.2)43 (41.4)
      Moderate (AHI 15–30)5 (13.2)18 (17.3)
      Severe (AHI > 30)0 (0)5 (4.8)
    PLMI (leg movements/hour)
      Negative (PLMI < 15)21 (55.3)49 (47.1)
      Low (PLMI 15–45)7 (18.4)33 (31.7)
      High (PLMI > 45)10 (26.3)22 (21.2)
    AV-45 PET SUVR1.44 (0.61)
    AV-1451 PET SUVR1.40 (0.49)
    Aβ42 (pg/ml)1012.59 (367.94)
    t-tau (pg/ml)245.46 (119.69)
    p-tau (pg/ml)23.66 (13.46)
    AD pathology
      Amyloid negative/tau negative20 (52.6)31 (29.8)
      Amyloid positive/tau negative9 (23.7)35 (33.7)
      Amyloid positive/tau positive8 (21.1)27 (25.9)
      Amyloid negative/tau positive1 (2.6)11 (10.6)
    Time interval from scan/lumbar puncture to sleep study (years)
      AV-45 PET0.29 (0.48)1.00 (2.60)
      AV-1451 PET0.29 (0.40)

    *For the participants who underwent PET imaging (N = 38), 4 of 38 participants used continuous positive airway pressure therapy during sleep monitoring. For participants with CSF (N = 104), 12 of 104 participants used continuous positive airway pressure therapy and 1 participant used lateral position therapy device during sleep monitoring.

    • Table 2 Relationship of NREM SWA to AV-1451 tau PET composite after adjusting for age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time.

      Linear mixed models were used to calculate the estimates and P values for the 38 participants with PET imaging. Time, longitudinal sleep monitoring.

      Dependent variableCovariateEstimateSEF statistic
      (df)
      P
      1–4.5 Hz SWAMean AV-1451 tau composite−8.8892.62511.46 (1,27)0.002
      Age−0.6700.2437.59 (1,28)0.010
      Sex−7.8502.6368.87 (1,28)0.006
      CDR−6.8823.3124.32 (1,29)0.047
      Race−9.2994.9503.53 (1,27)0.071
      ApoE4 status+4.0022.8911.92 (1,27)0.178
      Sleep medications+3.2254.4680.52 (1,27)0.476
      AHI+0.1410.1660.73 (1,28)0.401
      PLMI+0.1210.05375.09 (1,28)0.032
      Time+0.00010.1420.00 (1,145)0.999
      1–2 Hz SWAMean AV-1451 tau
      composite
      −21.4776.12312.30 (1,28)0.002
      Age−1.5390.5677.36 (1,28)0.011
      Sex−18.5426.1489.10 (1,28)0.005
      CDR−18.3397.7505.60 (1,29)0.025
      Race−21.62011.5373.51 (1,27)0.072
      ApoE4 status+9.0446.7321.80 (1,27)0.190
      Sleep medications+8.29810.4100.64 (1,27)0.432
      AHI0.3460.3870.80 (1,28)0.379
      PLMI0.2730.1254.76 (1,28)0.038
      Time0.0130.3550.00 (1,146)0.970
      2–3 Hz SWAMean AV-1451 tau
      composite
      −5.9191.9988.78 (1,28)0.006
      Age−0.5090.1867.51 (1,28)0.011
      Sex−5.5772.0097.71 (1,28)0.010
      CDR−3.6542.5002.14 (1,28)0.155
      Race−6.4963.7732.96 (1,28)0.096
      ApoE4 status+2.9252.2101.75 (1,28)0.197
      Sleep medications+1.7313.4100.26 (1,28)0.616
      AHI+0.0850.1260.46 (1,28)0.504
      PLMI+0.0920.0415.02 (1,28)0.033
      Time−0.0130.0950.02 (1,29)0.891
      3–4 Hz SWAMean AV-1451 tau
      composite
      −2.1860.7668.16 (1,27)0.008
      Age−0.1810.0716.44 (1,28)0.017
      Sex−2.0280.7726.90 (1,28)0.014
      CDR−1.1500.9571.44 (1,27)0.240
      Race−2.4061.4472.76 (1,27)0.108
      ApoE4 status+1.0040.8491.40 (1,28)0.247
      Sleep medications+0.4201.3080.10 (1,27)0.750
      AHI+0.0270.0480.32 (1,28)0.577
      PLMI+0.0350.0164.84 (1,28)0.036
      Time−0.0040.0380.01 (1,28)0.914
    • Table 3 Relationship of NREM SWA to AV-45 amyloid PET composite after adjusting for age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time.

      Linear mixed models were used to calculate the estimates and P values for the 38 participants with PET imaging.

      Dependent variableCovariateEstimateSEF statistic (df)P
      1–4.5 Hz SWAMean cortical AV-45
      amyloid composite
      −4.9262.4224.14 (1,28)0.052
      Age−0.6800.2706.36 (1,28)0.018
      Sex−8.5902.9488.49 (1,28)0.007
      CDR−3.4893.4631.02 (1,29)0.322
      Race−10.0035.5673.23 (1,27)0.083
      ApoE4 status+2.9463.3270.78 (1,27)0.384
      Sleep medications+3.1244.9630.40 (1,27)0.534
      AHI+0.1230.1830.45 (1,28)0.507
      PLMI+0.0840.0621.83 (1,28)0.187
      Time−0.0030.1420.00 (1,145)0.982
      1–2 Hz SWAMean cortical AV-45
      amyloid composite
      −12.0175.6764.48 (1,28)0.043
      Age−1.5630.6326.12 (1,28)0.020
      Sex−20.4016.9148.71 (1,28)0.006
      CDR−10.1388.1391.55 (1,29)0.223
      Race−23.32613.0413.20 (1,27)0.085
      ApoE4 status+6.4277.7860.68 (1,27)0.416
      Sleep medications−8.08611.6250.48 (1,27)0.493
      AHI+0.2990.4310.48 (1,28)0.493
      PLMI+0.1840.1461.59 (1,28)0.218
      Time+0.0030.3550.00 (1,146)0.994
      2–3 Hz SWAMean cortical AV-45
      amyloid composite
      −3.2391.8143.19 (1,28)0.085
      Age−0.5140.2026.48 (1,28)0.017
      Sex−6.0662.2057.57 (1,28)0.010
      CDR−1.4722.5680.33 (1,28)0.571
      Race−6.9364.1672.77 (1,28)0.107
      ApoE4 status+2.1962.4980.77 (1,28)0.387
      Sleep medications+1.6133.7160.19 (1,28)0.668
      AHI0.0730.1370.29 (1,28)0.598
      PLMI+0.0670.0462.09 (1,28)0.159
      Time−0.0140.0950.02 (1,29)0.886
      3–4 Hz SWAMean cortical AV-45
      amyloid composite
      −1.3500.6823.91 (1,28)0.058
      Age−0.1830.0765.80 (1,28)0.023
      Sex−2.2290.8307.21 (1,28)0.012
      CDR−0.3390.9630.12 (1,27)0.727
      Race−2.6451.5652.86 (1,27)0.102
      ApoE4 status+0.6820.9390.53 (1,28)0.474
      Sleep medications+0.4251.3960.09 (1,27)0.763
      AHI+0.0240.0510.21 (1,28)0.647
      PLMI+0.0240.0171.94 (1,28)0.175
      Time−0.0030.0380.01 (1,27)0.928
    • Table 4 Relationship of NREM SWA to Aβ42 after adjusting for age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time.

      Linear mixed models were used to calculate the estimates and P values for the 23 participants with CSF.

      Dependent variableCovariateEstimateSEF statistic
      (df)
      P
      1–4.5 Hz SWAAβ42+0.0040.0031.44 (1,10)0.257
      Age+0.0210.1880.01 (1,12)0.911
      Sex+0.4572.6870.03 (1,12)0.868
      CDR+8.2703.3046.27 (1,15)0.024
      Race−10.0313.9106.58 (1,10)0.029
      ApoE4 status−6.5972.8975.18 (1,11)0.044
      Sleep medications−17.9106.1028.62 (1,12)0.013
      AHI−0.0070.1510.00 (1,11)0.966
      PLMI+0.0550.0411.83 (1,13)0.199
      Time−0.1740.1671.08 (1,76)0.302
      1–2 Hz SWAAβ42+0.0080.0071.48 (1,11)0.248
      Age+0.0770.4470.03 (1,12)0.866
      Sex+0.9006.3940.02 (1,12)0.890
      CDR+18.0827.8735.28 (1,16)0.036
      Race−21.7159.3015.45 (1,11)0.040
      ApoE4 status−15.5656.8945.10 (1,12)0.044
      Sleep medications−44.69514.5249.47 (1,13)0.009
      AHI−0.0560.3600.02 (1,12)0.879
      PLMI+0.0860.0970.78 (1,14)0.393
      Time−0.4890.4011.49 (1,77)0.226
      2–3 Hz SWAAβ42+0.0030.0022.44 (1,9)0.153
      Age+0.0030.1280.00 (1,11)0.980
      Sex+0.2991.8460.03 (1,11)0.874
      CDR+7.2272.20310.76 (1,14)0.005
      Race−8.6542.7399.98 (1,8)0.013
      ApoE4 status−5.3722.0097.15 (1,10)0.024
      Sleep medications−13.9414.19811.03 (1,11)0.007
      AHI+0.0160.1050.02 (1,10)0.884
      PLMI+0.0590.0284.52 (1,12)0.054
      Time−0.0850.1250.47 (1,16)0.504
      3–4 Hz SWAAβ42+0.0020.0014.09 (1,12)0.066
      Age−0.0230.0720.10 (1,13)0.759
      Sex−0.2161.0270.04 (1,13)0.837
      CDR+2.6231.0745.97 (1,12)0.032
      Race−3.3011.5384.61 (1,12)0.053
      ApoE4 status−1.9641.1213.07 (1,13)0.104
      Sleep medications−6.3872.2677.94 (1,12)0.016
      AHI+0.0180.0580.10 (1,12)0.763
      PLMI+0.0240.0152.72 (1,13)0.124
      Time−0.0120.0520.06 (1,15)0.815
    • Table 5 Relationship of NREM SWA to tau/Aβ42 ratio after adjusting for age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time.

      Linear mixed models were used to calculate the estimates and P values for the 23 participants with CSF.

      Dependent variableCovariateEstimateSEF statistic
      (df)
      P
      1–4.5 Hz SWATau/Aβ42−10.7884.6735.33 (1,12)0.040
      Age+0.0340.1700.04 (1,12)0.846
      Sex+0.8382.3500.13 (1,12)0.728
      CDR+7.5672.8806.90 (1,14)0.020
      Race−13.8603.81813.18 (1,9)0.006
      ApoE4 status−6.9612.6456.92 (1,11)0.024
      Sleep medications−19.6975.56512.53 (1,12)0.004
      AHI+0.0560.1410.16 (1,11)0.699
      PLMI+0.0600.0372.59 (1,13)0.132
      Time−0.1540.1690.83 (1,70)0.365
      1–2 Hz SWATau/Aβ42−25.75711.0785.41 (1,13)0.038
      Age+0.1060.4030.07 (1,12)0.797
      Sex+1.5715.5710.08 (1,12)0.783
      CDR+16.4256.8075.82 (1,14)0.030
      Race−31.1339.07411.77 (1,10)0.007
      ApoE4 status−16.2166.2786.67 (1,12)0.025
      Sleep medications−49.38613.19614.01 (1,13)0.003
      AHI+0.1030.3330.10 (1,12)0.762
      PLMI+0.1000.08751.31 (1,13)0.272
      Time−0.4350.4061.15 (1,74)0.288
      2–3 Hz SWATau/Aβ42−11.5943.25112.72 (1,11)0.004
      Age+0.0080.1220.00 (1,12)0.952
      Sex+0.3431.6800.04 (1,12)0.842
      CDR+6.4311.76513.27 (1,8)0.006
      Race−12.5672.73921.06 (1,9)0.001
      ApoE4 status−5.9951.88910.07 (1,11)0.009
      Sleep medications−19.9443.81027.40 (1,10)0.0004
      AHI+0.0690.0970.50 (1,10)0.496
      PLMI+0.0580.0255.28 (1,11)0.042
      Time−0.0820.1290.41 (1,17)0.533
      3–4 Hz SWATau/Aβ42−5.5491.68710.82 (1,10)0.008
      Age−0.0190.0640.09 (1,11)0.773
      Sex−0.0010.8780.00 (1,11)0.999
      CDR+2.2230.9115.95 (1,10)0.036
      Race−5.0761.40313.08 (1,8)0.006
      ApoE4 status−2.1040.9784.63 (1,10)0.057
      Sleep medications−6.7841.96511.92 (1,9)0.007
      AHI+0.0400.0500.64 (1,10)0.444
      PLMI+0.0290.0134.78 (1,10)0.053
      Time−0.0190.0530.13 (1,15)0.719

    Supplementary Materials

    • www.sciencetranslationalmedicine.org/cgi/content/full/11/474/eaau6550/DC1

      Fig. S1. Relationship between NREM SWA and tau PET varies by region when uncorrected for multiple comparisons.

      Fig. S2. Relationship between NREM SWA and amyloid PET varies by region when uncorrected for multiple comparisons.

      Table S1. Group differences in average sleep parameters between amyloid negative/positive, tau negative/positive, and CDR 0/0.5 for participants with PET imaging.

      Table S2. Group differences in average sleep parameters between amyloid negative/positive, tau negative/positive, and CDR 0/0.5 for participants with CSF.

      Table S3. Relationship of NREM SWA power to AV-1451 tau PET regions after adjusting for age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time.

      Table S4. Relationship of NREM SWA to AV-45 amyloid PET regions after adjusting for age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time.

      Table S5. Relationship of NREM SWA to p-tau/Aβ42 ratio after adjusting for age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time.

      Table S6. Relationship of sleep parameters to AV-45 amyloid and AV-1451 tau PET after adjusting for age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time.

      Table S7. Relationship of sleep parameters to tau/Aβ42 ratio after adjusting for age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time.

    • This PDF file includes:

      • Fig. S1. Relationship between NREM SWA and tau PET varies by region when uncorrected for multiple comparisons.
      • Fig. S2. Relationship between NREM SWA and amyloid PET varies by region when uncorrected for multiple comparisons.
      • Table S1. Group differences in average sleep parameters between amyloid negative/positive, tau negative/positive, and CDR 0/0.5 for participants with PET imaging.
      • Table S2. Group differences in average sleep parameters between amyloid negative/positive, tau negative/positive, and CDR 0/0.5 for participants with CSF.
      • Table S3. Relationship of NREM SWA power to AV-1451 tau PET regions after adjusting for age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time.
      • Table S4. Relationship of NREM SWA to AV-45 amyloid PET regions after adjusting for age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time.
      • Table S5. Relationship of NREM SWA to p-tau/Aβ42 ratio after adjusting for age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time.
      • Table S6. Relationship of sleep parameters to AV-45 amyloid and AV-1451 tau PET after adjusting for age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time.
      • Table S7. Relationship of sleep parameters to tau/Aβ42 ratio after adjusting for age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time.

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